PRIORITY COMMUNICATION The Relationship Between Dorsolateral Prefrontal N- Acetylaspartate Measures and Striatal Dopamine Activity in Schizophrenia* Alessandro Bertolino, Michael B. Knable, Richard C. Saunders, Joseph H. Callicott, Bhaskar Kolachana, Venkata S. Mattay, Jocelyne Bachevalier, Joseph A. Frank, Michael Egan, and Daniel R. Weinberger Background: Pathology of dorsolateral prefrontal cortex and dysregulation of dopaminergic neurons have been associated with the pathophysiology of schizophrenia, but how these phenomena relate to each other in patients has not been known. It has been hypothesized that prefrontal cortical pathology might induce both diminished steady- state and exaggerated responses of dopaminergic neurons to certain stimuli (e.g., stress). We examined the relation- ship between a measure of prefrontal neuronal pathology and striatal dopamine activity in patients with schizophre- nia and in a nonhuman primate model of abnormal prefrontal cortical development. Methods: In the patients, we studied in vivo markers of cortical neuronal pathology with NMR spectroscopic im- aging and of steady-state striatal dopamine activity with radioreceptor imaging. In the monkeys, we used the same NMR technique and in vivo microdialysis. Results: Measures of N-acetyl-aspartate concentrations (NAA) in dorsolateral prefrontal cortex strongly and selectively predicted D 2 receptor availability in the stria- tum (n = 14, rho =-.64, p  .01), suggesting that the greater the apparent dorsolateral prefrontal cortex pa- thology, the less the steady-state dopamine activity in these patients. A similar relationship between NAA mea- sures in dorsolateral prefrontal cortex and steady-state dopamine concentrations in the striatum was found in the monkeys (n = 5, rho = .70, p  .05). We then tested in the same monkeys the relationship of prefrontal NAA and striatal dopamine overflow following amphetamine infu- sion into dorsolateral prefrontal cortex. Under these conditions, the relationship was inverted, i.e., the greater the apparent dorsolateral prefrontal cortex pathology, the greater the dopamine release. Conclusions: These data demonstrate direct relationships between putative neuronal pathology in dorsolateral pre- frontal cortex and striatal dopamine activity in human and nonhuman primates and implicate a mechanism for dopa- mine dysregulation in schizophrenia. Biol Psychiatry 1999;45:660 – 667 © 1999 Society of Biological Psychia- try Key Words: N-acetylaspartate, dorsolateral prefrontal cortex, striatum, dopamine, radio-receptor imaging, mi- crodialysis *See accompanying Editorial, in this issue. Introduction S chizophrenia has been associated with numerous claims of abnormalities in the brain but the basic neurobiology of the disorder remains a mystery. Of the many reported findings, two lines of research data have emerged as particularly prominent, involving pathology of dorsolateral prefrontal cortex and dopamine dysregulation. Abnormal dorsolateral prefrontal cortical function has been implicated in a number of neuropsychological and neuroimaging studies (Weinberger et al 1986, 1987; Braff et al 1991; Goldberg and Gold 1995; Andreasen et al 1994; Frith et al 1995). Moreover, post-mortem tissue studies have found evidence of subtle pathology of dorso- lateral prefrontal cortex and its connectivity (Selemon et al 1995; Lewis 1997; Perrone-Bizzozzero 1996; Rajkowska et al 1998). Dysregulation of the dopamine system has long been inferred, based on the fact that dopamine receptor antagonists alleviate certain symptoms (e.g., de- lusions, hallucinations), whereas dopamine agonists exag- gerate them in afflicted patients (Peroutka and Snyder 1980; Lieberman et al 1987; Carlsson 1995). Until rela- tively recently, the possibility that pathology of dorsolat- eral prefrontal cortex and dopamine dysregulation might be directly related phenomena received little attention. However, animal studies have shown that prefrontal cortex From the Clinical Brain Disorders Branch, Intramural Research Programs, National Institute of Mental Health, NIH Bethesda, MD, Department of Neurobiology and Anatomy, University of Texas, Houston, TX (JB); and the Laboratory of Diagnostic Radiology Research, OD, NIH (JAF) Address reprint requests to Daniel R. Weinberger, MD, Clinical Brain Disorders Branch, NIMH, 10 Center Drive, Room 45235 MSC 1379, Bethesda, MD 20892. Received September 23, 1998; revised December 4, 1998; accepted December 9, 1998. © 1999 Society of Biological Psychiatry 0006-3223/99/$19.00 PII S0006-3223(98)00380-1